Nasal Delivery of Engineered Exosomes via a Thermo‐Sensitive Hydrogel Depot Reprograms Glial Cells for Spinal Cord Repair

Spinal cord injury (SCI) presents formidable therapeutic challenges due to its multifaceted pathological complexity. Here, this work reports engineered macrophage-derived exosomes overexpressing GNA12 and GNA13 (G12G13MExos) that reprogram macrophages toward the M2c anti-inflammatory phenotype and astrocytes into a neuroprotective phenotype. G12G13MExos enhance astrocyte-mediated clearance of myelin debris, glutamate homeostasis, and synapse formation while fostering astrocyte-neuron crosstalk. These effects improve neuronal survival and drove neural stem cell differentiation into V2a neurons, facilitating neural circuit reconstruction. This work develops a chitosan-based thermosensitive hydrogel that functions as a "nasal exosome intelligent slow-release depot" to enable efficient and targeted exosome delivery. This delivery system bypasses hepatic and renal sequestration and overcomes the blood-spinal cord barrier, significantly enhancing therapeutic efficacy. This strategy integrates engineered exosomes with a responsive delivery platform, modulating the inflammatory microenvironment, enhancing cellular crosstalk, and promoting neural repair. This comprehensive approach offers a promising translational avenue for SCI treatment and other central nervous system disorders.